In the fetus, pulmonary vascular resistance is high, in part due to active vasoconstriction of the small pulmonary arteries induced by leukotrienes or other vasoconstricting substances. At birth, with the initiation of ventilation, pulmonary vascular resistance decreases to allow an increased pulmonary blood flow. Prostacyclin and prostaglandin D2 may mediate these changes. In several clinical conditions, the normal fall in pulmonary vascular resistance does not occur with the initiation of ventilation at birth, resulting in persistent pulmonary hypertension, right-to-left shunting of blood, and hypoxemia. The treatment of these infants is largely supportive. If selective pulmonary vasodilation could bc achieved, the present mortality rate of 20-50% might decline. There are anatomic changes in the small pulmonary arteries of those infants who died strongly suggesting that in utero events have altered the pulmonary circulation prior to birth. These changes are not restricted to the pulmonary circulation, since infants with pulmonary hypertension also have elevated systemic vascular resistance and show evidence of cardiac dysfunction. In a model of persistent pulmonary hypertension produced by long-term (chronic) umbilical cord compression in fetal lambs, PaO2 is decreased and PaCO2 is increased. When these lambs are ventilated at birth, pulmonary vascular resistance and pulmonary arterial pressure do not fall normally and they demonstrate an exaggerated response to alveolar hypoxia. In addition, these lambs have excessive muscularization of the small pulmonary arteries, similar to infants with persistent pulmonary hypertension. Using this model, this project has several aims: (1) to examine the hemodynamic effects of chronic umbilical cord compression on the pulmonary and systemic circulations in the fetal lamb; concentrations of potential mediators of pulmonary and systemic vasoconstriction (leukotrienes, thromboxane, catecholamines and arginine vasopressin) will be measured and the hemodynamic effects of their selective inhibition will be studied; (2) to study the hemodynamic effects of superimposed acute fetal stress because acute stress responses are probably modified by previous chronic stress; (3) to evaluate the effects of ventilation, potentially specific vasoconstricting substances and inhibition of vasoconstricting substances on the pulmonary circulation after chronic umbilical cord compression; and (4) to assess left ventricular systolic and diastolic performance. A better understanding of the in utero events producing the various circulatory changes associated with persistent pulmonary hypertension will lead to improved treatment of these infants and, possibly, prevention of the disorder.